VALCLOV 500

Quick Overview

Our aim is to reach out to the globe within shortest possible time frame.

To promote this objective, not only we distribute and market our Anti viral range of products globally through our distribution channels but we also undertake ‘contract manufacturing’& ‘formulation development ’of our wide range of generic products such as VALCLOV 500 which contains Valacyclovir ...500 mg.

Description : Blue colour Caplet Shape Film-coated Tablets breakline on one side and plain on other side.

ACTIONS AND CLINICAL PHARMACOLOGY

Mechanism of action

Valacyclovir an antiviral is the L-valine ester of Acyclovir. Acyclovir is a purine (guanine) nucleoside analogue. Valacyclovir is rapidly and almost completely converted in man to acyclovir and valine, probably by the enzyme referred to as valacyclovirhydrolase. Acyclovir is a specific inhibitor of the herpes viruses with in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), and human herpes virus 6 (HHV-6). Acyclovir inhibits herpes virus DNA synthesis once it has been phosphorylated to the active triphosphate form. The first stage of phosphorylation requires the activity of a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only present in virus-infected cells. Selectivity is maintained in CMV with phosphorylation, at least in part, being mediated through the phosphotransferase gene product of UL97. This requirement for activation of aciclovir by a virus-specific enzyme largely explains its selectivity.

Resistance to acyclovir is normally due to a thymidine kinase deficient phenotype which results in a virus which is disadvantaged in the natural host. Reduced sensitivity to acyclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants resembles that of the wild-type virus.

Monitoring of clinical HSV and VZV isolates from patients receiving acyclovir therapy or prophylaxis has revealed that virus with reduced sensitivity to acyclovir is extremely rare in the immunocompetent host and is found infrequently in severely immunocompromised individuals e.g. organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).

Pharmacokinetic Actions

Absorption: Valacyclovir is a pro-drug of acyclovir. The bioavailability of acyclovir from valacyclovir is about 3.3 to 5.5-fold greater than that historically observed for oral acyclovir. After oral administration valacyclovir is well absorbed and rapidly and almost completely converted to acyclovir and valine. This conversion is probably mediated by an enzyme isolated from human liver referred to as valacyclovir hydrolase. The bioavailability of acyclovir from 1000 mg valacyclovir is 54%, and is not reduced by food.

Distribution: Binding of valacyclovir to plasma proteins is very low (15%). CSF penetration, determined by CSF/plasma AUC ratio, is independent of renal function and was about 25% for acyclovir and the metabolite 8-OH-ACV, and about 2.5% for the metabolite CMMG.

Biotransformation: After oral administration, valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to the metabolites 9(carboxymethoxy) methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxy-aciclovir (8-OH-ACV) by aldehyde oxidase. Approximately 88% of the total combined plasma exposure is attributable to acyclovir, 11% to CMMG and 1% to 8-OH-ACV. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes.

Elimination: Valacyclovir is eliminated in the urine principally as acyclovir (greater than 80% of the recovered dose) and the acyclovir metabolite CMMG (about 14% of the recovered dose). The metabolite 8-OH-ACV is detected only in small amounts in urine (< 2% of the recovered dose). Less than 1% of the administered dose of valacyclovir is recovered in the urine as unchanged drug. In patients with normal renal function the plasma elimination half-life of acyclovir after both single and multiple dosing with valacyclovir is approximately 3 h.

INDICATIONS

• For the treatment of herpes zoster (shingles) in adult patients who commence therapy within 72 hours of the onset of rash.

• For the treatment of ophthalmic zoster.

• For the treatment of recurrent herpes labialis (cold sores)

• For the treatment of clinical episodes of genital herpes simplex infections.

• For the prevention of recurrent genital herpes.

• Reduction of transmission of genital herpes in patients suffering from recurrent genital herpes. In addition to therapy with Valacyclovir, it is recommended that patients use safer sex practices.

• Prophylaxis of cytomegalovirus (CMV) infection and disease following solid organ transplantation in patients at risk of CMV disease.

DOSAGE AND ADMINISTRATION:

Dosage in Adults

• For treatment of herpes zoster, 1000 mg of Valacyclovir three times a day for seven days.

• The recommended dosage of Valacyclovir for the treatment of cold sores is 2000 mg twice daily for 1 day with the second dose taken about 12 hours (no sooner than 6 hours) after the first dose. Therapy should be initiated at the earliest symptom of a cold sore (e.g. tingling, itching, or burning).

• For treatment of first clinical presentation of genital herpes, 500 mg of Valacyclovir twice a day for 5 to 10 days.

• For recurrent episodes of genital herpes, 500 mg twice daily for 5 days. Dosing should begin as early as possible. For recurrent episodes of genital herpes, this should ideally be during the prodromal period or immediately following the appearance of the first signs or symptoms.

• For the prevention of genital herpes in patients with a history of fewer than 10 recurrences each year, 500mg of Valacyclovir once daily, either as a single dose or a divided dose.

• For the prevention of genital herpes in patients with a history of 10 or more recurrences each year when not taking suppressive therapy, 1000mg of Valacyclovir once daily.

• For immunocompromised patients, 500 mg twice daily.

• Reduction of transmission of genital herpes: In immunocompetent heterosexual adults with less than 10 recurrences per year and with the susceptible partner discordant for HSV-2 antibodies, 500mg of Valacyclovir to be taken once daily by the infected partner.

(There are no data on the reduction of transmission in other patient populations)

• For the prophylaxis of cytomegalovirus infection (CMV) and disease: Dosage of Valacyclovir in adults and adolescents (from 12 years of age) is 2 g four times a day for 90 days, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see Dosage in renal impairment).

Dosage in renal impairment

Caution is advised when administering Valacyclovir to patients with impaired renal function.

Adequate hydration should be maintained.

Treatment of herpes zoster and genital herpes simplex: The dose of Valacyclovir should be modified as follows in patients with significantly impaired renal function:

Treatment of herpes labialis: The dose of Valacyclovir should be modified as follows in patients with significantly impaired renal function:

Creatinine Clearance Valacyclovir Dosage

≥ 50 mL/min 2000 mg twice a day

31 – 49mL/min 1000 mg twice a day

15-30 mL/min 500 mg twice a day

< 15 mL/min 500 mg single dose

In patients on hemodialysis the Valacyclovir dose recommended for patients with a creatinine clearance of less than 15 mL/min should be used, but the dose should be administered after the hemodialysis has been performed.

CMV prophylaxis: The dosage of Valacyclovir should be adjusted in patients with impaired renal function as shown in the table below:

Creatinine clearance ml/min Valacyclovir dosage

75 or greater 2 g four times daily

50 to less than 75 1.5 g four times a day

25 to less than 50 1.5 g three times a day

10 to less than 25 1.5 g twice a day

less than 10 or dialysis◊ 1.5 g once a day

◊ In patients on hemodialysis, the Valacyclovir dosage should be administered after the hemodialysis has been performed. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The dosage should be adjusted accordingly.

Dosage in hepatic impairment

Studies with a 1 g unit dose of Valacyclovir show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis, (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment; however clinical experience is limited. For higher doses recommended for CMV prophylaxis see (Warnings and Precautions).

CONTRAINDICATIONS

Hypersensitivity to valacyclovir or acyclovir or any of the excipients

WARNINGS & PRECAUTIONS

Hydration status: Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.

Use in patients with renal impairment and in elderly patients: Acyclovir is eliminated by renal clearance; therefore the dose of valacyclovir must be reduced in patients with renal impairment. Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side-effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment.

Use of higher doses of valacyclovir in hepatic impairment and liver transplantation: There are no data available on the use of higher doses of valacyclovir (4000 mg or more per day) in patients with liver disease. Specific studies of valacyclovir have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000 mg to these patients.

Use for zoster treatment: Clinical response should be closely monitored, particularly in immunocompromised patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient. Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebro-vascular complications should be treated with intravenous antiviral therapy. Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.

Transmission of genital herpes: Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. During suppressive treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. Therefore, in addition to therapy with valacyclovir, it is recommended that patients use safer sex practices.

Use in ocular HSV infections: Clinical response should be closely monitored in these patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.

Use in CMV infections: Data on the efficacy of valacyclovir from transplant patients (~200) at high risk of CMV disease (e.g. donor CMV-positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valacyclovir should only be used in these patients when safety concerns preclude the use of valacyclovir or gancyclovir. High dose valacyclovir as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications. Patients should be closely monitored for changes in renal function, and doses adjusted accordingly.

Use in Pregnancy: A study of the pharmacokinetics of valacyclovir and acyclovir during late pregnancy indicates that pregnancy does not affect the pharmacokinetics of valacyclovir.

Nursing Mothers: Following oral administration of a 500 mg dose of valacyclovir, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times the corresponding maternal acyclovir serum concentrations. The median acyclovir concentration in breast milk was 2.24 micrograms/ml (9.95 micromoles/L). With a maternal valacyclovir dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral acyclovir dosage of about 0.61 mg/kg/day. The elimination half-life of acyclovir from breast milk was similar to that for serum. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine.

Use in Children: The efficacy of valacyclovir in children below the age of 12 years has not been evaluated.

DRUG INTERACTIONS

The combination of valacyclovir with nephrotoxic medicinal products should be made with caution, especially in subjects with impaired renal function, and warrants regular monitoring of renal function. This applies to concomitant administration with aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, cyclosporine, and tacrolimus.

Following 1000 mg valacyclovir, cimetidine and probenecid reduce acyclovir renal clearance and increase the AUC of acyclovir by about 25% and 45%, respectively, by inhibition of the active renal secretion of acyclovir. Cimetidine and probenecid taken together with valacyclovir increased acyclovir AUC by about 65%. Other medicinal products (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase acyclovir concentrations by this mechanism. Similarly, valacyclovir administration may increase plasma concentrations of the concurrently administered substance.

Increases in plasma AUCs of acyclovir and of the inactive metabolite of mycophenolate motefil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are co-administered. No changes in peak concentrations or AUCs are observed with co- administration of valaciclovir and mycophenolate mofetil in healthy volunteers. There is limited clinical experience with the use of this combination.

The pharmacokinetics of digoxin were not affected by co-administration of valacyclovir hydrochloride1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride(1 gram) was unchanged by co-administration of digoxin (2 doses of 0.75 mg).

Symptoms and Signs: Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

Treatment: Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.